Process for preparing n-(2-hydroxyethyl)-n-(lower-alkyl)-9-aminomethylanthracenes and intermediates therein



United States Patent PROCESS FOR PREPARING N (2 HYDROXY- ETHYL) N (LOWER ALKYL) 9 AMINO- METHYLANTHRACENES AND INTERMEDI- ATES THEREIN Chester H. Bolen, Drug Inc., New ware No Drawing. Application March 23, 1956 Serial No. 573,352

Claims. (Cl. 260-307) Delmar, N. Y., assignor to Sterling York, N. Y., a corporation of Delaparticular the invention concerns a new process for preparing N-(Z-hydroxyethyl)-N-(lower-alkyl)- 9-aminomethylanthracenes and to novel 3-(lower-alkyl) oxazolidines having a 9-anthryl substituent in the 2-position which are employed as intermediates in said process. (2 hydroxyethyl)-N-(lower-alkyl)-9-aminomethylanthracenes produced by my new process are de- Patent 2,734,920, issued as antifibrillatory agents and as intermediates in preparing adrenolytic agents.

My new process comprises heating 9-anthraldehyde (I) with an N-(lower-alkyl)-2-hydroxyethylamine (II), and hydrogenolyzing the resulting 2-(9-anthryl)-3-(1oweralkyl)-oxazolidine (III) to give an N-(Z-hydroxyethyD- v tion of an excess of 2,865,925 Patented Dec. 23, 1958 of the oxygen-carbon bond in the 1,2-position of an oxazolidine ring benzene, ether, etc., which is inert under the conditions of the reaction. The N-(2-hydroxyethyl)-N-(lower-alkyl)- 9-aminomethylanthracene is conveniently isolated in the form of a crystalline acid-addition salt obtained by addia strong acid to a solution of the free base.

The following examples will further illustrate the invention without limitingthe same thereto.

EXAMPLE 1 i N Z-hydroxyethyl -N -ethyl-9-aminomethylanthracene N-(lower-alkyl)-9-aminomethylanthracene (IV), according to the following equations:

which atoms and can be straight or branched, thus including such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.

The first step of the process comprises heating anthraldehyde with an N-(lower-alkyl)-2-hydroxyethylamine. Equimolar quantities of the aldehyde and amine, or if desired a slight excess preferably at a temperature between about 50 C. and

The second step of the process comprises hydrogenolyzing the 2-(9-anthryl)-3-(lower-alkyl)oxazolidine prohydrochloride A mixture of 20.6 g. 0.1 mole) of 9-anthraldehyde mole) of N-ethyl-2-hydroxyethylamine Iected. An additional 5 ml. of N-ethyl-Z-hydroxyethylamine was then added and the mixture heated for thirty The reaction mixture was allowed to stand at hours, and was then which upon cooling deposited 15.5 g. of 6-(2-hydroxyethyl)-N-ethyl-9-aminomethylanthracene hydrochloride, M. P. 213-214 C. Upon concentration of the mother liquors a second crop of 4.5 g., M. P. 209-210 C., was

extracted with ether. tion gave a fourth crop total yield 21.7 g. (69% By substitution in the preceding example of the N-ethyl- 2-hydroxyethylamine by a molar equivalent amount of N-methyl- -11ydroxyethylamine, N-propyl-Z-hydroxyethylamine, N-isopropyl-Z-hydroxyethylamine, .N-butyl-2-hydroxyethylamine, N-isobutyl-2-hydroxyethylamine, N-

, tertiary-butyl-Z-hydroxyethylamine, N-pentyl-2-hydroxyethylamine, N-hexyl-2-hydroxyethylamine, or N-isohexyl- 2-hydroxyethylamine, there can be obtained, respectively, N (2 hydroxyethyl) N methyl-9-aminomethylanthracene, N- (2-hydroxyethyl)-N-propyl-9-aminomethylanthracene, N (2 hydroxyethyl) -N-isopropyl-9-aminomethylanthracene, N-(Z-hydroxyethyl)-N-butyl-9-aminomethylanthracene, N (2 hydroxyethyl) N-isobutyl-9-aminomethylanthracene, N (Z-hydroxyethyl)-N-tertiary-butyl- 9-aminomethylanthracene, N-(Z-hydroxyethyl)-N-penty1e EXAMPLE 2 2-(9-anthryi) -3- ethyloxaz0lidine hydrochloride A mixture of 10.3 g. of 9-anthraldehycle and 4.5 g. of N-ethyl-Z-hydroxyethylamine was heated on a steam bath under water pump vacuum for two and one-half hours. The reaction mixture containing 2-(9-anthryl)-3-ethyloxazolidine was then dissolved in about 60 ml. of warm isopropyl alcohol and acidified with alcoholic hydrogen chloride. The crystalline product which separated upon cooling was collected by filtration, washed with isopropyl alcohol, recrystallized from methanol and dried in vacuo, giving 2-(9-anthryl)-3-ethyloxazolidine hydrochloride in the form of yellow crystals, M. P'. 208.5-211.5 C. (corn).

Analysis.-Calcd. for C H ClNOz C, 72.80; H, 6.43; Cl, 11.30. Found: C, 73.09; H, 6.51;Cl, 11.13.

By substitution in the preceding example of the N- ethyl-Z-hydroxyethylamine by a molar equivalent amount of N-methyl-2-hydroxyethylamine, N-propyl-Z-hydroxyethylamine, N-isopropyl-Z-hydroxyethylamine, Nbuty1-2- hydroxyethylamine, N-isobutyl-Z-hydroxyethylamine, N- tertiary-butyl-2-hydroxyethylamine, N-pentyl-2-hydroxyethylamine, N-hexyl-Z-hydroxyethylamine, or N-isohexyl- 2-hydroxyethylamine, there can be obtained, respectively, 2-(9-anthryl) -3-methyl0xazolidine, 2- 9-anthryl) -3 -propyloxazolidine, 2-(9-anthryl)-3-isopropyloxazolidine, 2- (9-anthryl) -3-butyloxazolidine, 2- (9-anthryl) -3-isobutyloxazolidine, 2-(9-anthryl)-3-tertiary-butyloxazolidine, 2- (9-anthryl) -3 -pentyloxazolidine, 2- (9-anthryl) -3-hexyloxazolidine, or 2 (9-anthryl)-3-isohexyloxazolidine.

By substitution in the preceding example of the alcoholic hydrogen chloride by alcoholic solutions of hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, or methanesulfonic acid, there can be obtained, respectively, the hydrobromide, 'hydriodide, sulfate (or bisulfate), phosphate (or acid phosphate), or methanesulfonate salts of 2-(9-anthryl)-3-ethyloxazolidine.

Iclaim:

l. The process for preparing an N-(2-hydroxyethyl')- N-(lower-alkyl)-9-arninomethylanthracene, which comprises heating 9-anthraldehyde with an N-(lower-alkyh- Z-hydrOXyethyl-amine to produce a 2-(9-anthryl)-3-(loweralkyl)oxazolidine, and thereafter hydrogenolyzing the latter.

2. The process for preparing a 2-(9-anthryl) -3-(loweralkyDoxazolidine, which comprises heating 9-anthraldehyde with an N-(lower-alkyl)-2-hydroxyethylamine.

3. The process for preparing an N-(Z-hydroxyethyD- N-lower-alkyl)-9-aminomethylanthracene, which comprises hydrogenolyzing a 2-(9-anthryl)-3-(lower-alkyl) oxazolidine.

4. The process for preparing N-(2-hydroxyethyl)-N- ethyl-9-aminomethylanthracene, which comprises heating 9-anthraldehyde with N-ethyl-2-hydrexyethylamine to produce 2-(9-anthryl)-3-ethyloxazolidine, and thereafter hydrogenolyzing the latter.

5. The process for preparing 2-(9-anthryl)-3-ethy1- oxazolidine, which comprises heating 9-anthraldehyde with N-ethyI-Z-hydroxyethylamine.

6. The process for preparing N-(Z-hydroXyethyl'yN- ethyl-9-aminomethylanthracene, which comprises hydrogenolyzing 2-(9-anthryl)-3-ethyloxazolidine.

7. A compound selected from the group consisting of 2-(9-anthryl)-3-lower-alkyl).oxazolidines having the formula References Cited in the file of this patent UNITED STATES PATENTS 2,194,294 Cass et a1 Mar. 19, 1940 2,194,314 Maxwell Mar. 19, 1940 2,734,920 Hunter et al Feb. 14, 1956 UNITED STATES PATENT OIFFICE CERTIFICATE OF CORRECTION Patent No, 2,865,925 December 23, 1958 Chester H, Bolen It is hereby certified that error appears in the-printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 47, for =-(2-hydroxy=" read N-(2 hydroxy col mn 4, line 8, for "N-=loWer==alkyl) read N- (lower=-alkyl)== line 23, for "-3=-loWer-alkyl) read -3- (loWer-alkyl) Signed and sealed this 31st day of March 1959.,

(SEAL) Attest:

KARL H, AXLINE ROBERT C. WATSON Attesting Oflicer Commissioner of Patents 

1. THE PROCESS FOR PREPARING AN N-(2-HYDROXYETHYL)N-(LOWER-ALKYL)-9-AMINOMETHYULANTHRACENE, WHICH COMPRISES HEATING 9-ANTHRALDEHYDE WITH AN N-(LOWER-ALKYL)2-HYDROXYETHYLAMINE TO PRODUCE A 2-(9-ANTHRYL)-3-(LOWERALKYL)OXAZOLIDINE, AND THEREAFTER HYDROGENOLYZING THE LATTER.
 7. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 2-(9-ANTHRYL)-3-LOWERD-ALKYL)OXAZOLIDINES HAVING THE FORMULA 